METHOD OF PRODUCING HIGH-CONCENTRATED TECHNETIUM-99m SOLUTION IN LARGE QUANTITIES

ABSTRACT

A method of producing high concentrated  99m Tc solution has the steps of dissolving  99 MoO 3  pellet with alkali solution; extracting  99m Tc from the dissolved solution with ketone type organic solvent; separating an ketone type organic phase containing  99m Tc and an aqueous phase; adsorbing and concentrating the separated ketone type organic phase containing  99m Tc after removing impurities, through a basic alumina column for impurity removal and an acidic alumina column for adsorption and concentration connected continuously; and eluting  99m Tc from the acidic alumina column to which  99m Tc is adsorbed by physiological saline, wherein the alkali solution is 6M-NaOH solution or 6M-KOH solution.

BACKGROUND OF THE INVENTION

The present invention relates to a method of producing high concentrated technetium-99m (^(99m)Tc) solution in large quantities and in a short time, which is used as technetium-99m pharmaceutical products in general.

^(99m)Tc is widely used for the nuclear medicine diagnosis in the world. ^(99m)Tc is usually obtained from the generator on which molybdenum-99 (⁹⁹Mo) which ketone type organic solventis the parent nuclide is adsorbed. In general, ^(99m)Tc pharmaceutical products are produced with a small generator or supplied directly from a medicine maker as ^(99m)Tc pharmaceutical products in a hospital etc. (For instance, refer to patent literature 1) though ^(99m)Tc pharmaceutical products are produced with a large-scale generator in the medicine maker.

Though ^(99m)Tc is generated with β-decay of ⁹⁹Mo which is the parent nuclide, the enriched uranium is used as a raw material in a conventional ⁹⁹Mo production method, and ⁹⁹Mo is extracted through complex processes after irradiating the enriched uranium in a nuclear reactor (hereafter, (n,f) method). Non-patent literature 1 discloses the outline of the method of producing a large amount of ^(99m)Tc which exceeds 100 Ci (3.7 TBq) on a commercial basis from the ⁹⁹Mo produced by ⁹⁸Mo (n,y) ⁹⁹Mo reaction (hereafter, (n,y) method). In the method disclosed in the non-patent literature 1, 250 g (specific radioactivity 1 Ci (3.7×10¹⁰ Bq)/gMoO₃) obtained by irradiating neutrons to molybdenum trioxide is dissolved to KOH solution. The solution is babbled by air under the temperature environment of 90-95° C. to prevent precipitation by reduction, and ^(99m)Tc is extracted into methyl ethyl ketone (MEK) by stirring to babble after adding MEK. This extracted solution is moved to an evaporator after separating from the aqueous phase, and the MEK is evaporated to dryness by heating. Remaining ^(99m)Tc is dissolved by physiological salt solution to make a product.

Moreover, the laboratory-scale ^(99m)Tc production unit which is a basic production unit for carrying out the method according to the present invention is disclosed in non-patent literature 2. The production unit disclosed in this document is provided with a basic alumina column and an acidic alumina column connected in series with each other at the final stage to extract high quality ^(99m)Tc. Wherein, after removing the impurities such as ⁹⁹Mo in the basic alumina column, and making an acidic alumina column adsorb ^(99m)Tc, the MEK is removed from the acidic alumina column by using water, and the ^(99m)Tc is eluted with physiological saline.

[Patent literature 1] JP 2011-105567 A

[Non-patent literature 1] R. E. BOYD, Radiochimica Acta, 30, and 123-145 (1982).

[Non-patent literature 2] Sankha Chattopadhyay et al. Appl. Radiat. Isot, 68, 1-4 (2010).

BRIEF SUMMARY OF THE INVENTION Problems to be Solved by the Invention

⁹⁹Mo of the parent nuclide of ^(99m)Tc is produced by an (n,f) method in which the nuclear fission of ²³⁵U in a nuclear reactor is used. ⁹⁹Mo having the specific radioactivity above 370 TBq·g⁻¹ is obtained in this (n,f) method. However, there are some problems that the nuclear fuel is treated, it is necessary to separate ⁹⁹Mo from various types of fission products generated voluminously, and the majority of fission products containing uranium becomes the radioactive waste as it is.

Therefore, the neutron activation method in which the neutron capture reaction of ⁹⁸Mo in a nuclear reactor is used is adopted as one of the strategies to obtain ⁹⁹Mo in the present invention. This method adopts the (n,y) method in which neutrons and ⁹⁸Mo which exists in nature Mo by about 24% are used, and has merits such as little generation of the radioactive waste, easy production process and easy radiation shield. However, There is a fault that the specific radioactivity of ⁹⁹Mo obtained is less than or nearly equal to 74 GBq·g−1 four digits smaller than the (n,f) method. It is, therefore, required to devise to use as a small generator, and its use is limited. As a result, it has been tried to obtain a large amount of high concentrated ^(99m)Tc for ^(99m)Tc pharmaceutical products supplied from a medicine maker by using the (n,y) method.

The outline of a (n,y) method of producing a large amount of ^(99m)Tc which exceeds 100 Ci (3.7 TBq) in commercial production has been described in non-patent literature 1 mentioned above. However, this method needs a long time for the evaporation operation of MEK which contains ^(99m)Tc after extraction. Moreover, some products obtained might be colored, because a certain amount of the aqueous phase component may be incorporated into the products during the phase separation of MEK. Therefore, it is desirable to avoid such evaporation operation.

An alumina column which has the function to remove the aqueous phase is used in the production unit disclosed in non-patent literature 2 mentioned above. Therefore, the product obtained is not colored, and thus high quality ^(99m)Tc solution can be obtained. However, it is still a production unit at the laboratory scale, and cannot obtain a large amount of products. That is, the amount of handling in this production unit is 500 mCi (18.5 GBq) at most. Accordingly, various research and development is requested to produce a large amount of high concentrated ^(99m)Tc in a short time.

An object of the present invention is to provide a method of producing high concentrated technetium-99m (^(99m)Tc) solution in large quantities and in a short time, in which the quantity and the concentration of ^(99m)Tc produced per unit time is remarkably improved as compared to the prior art, and thus it is possible to put to practical use.

Means for Solving the Problems

The inventors succeeded to obtain ^(99m)Tc with TBq of radioactivity different from GBq of the radioactivity of conventional ^(99m)Tc by improving drastically the production method in the Production unit similar to the conventional one, in which the alkali concentration of the solution for dissolving molybdenum trioxide (MoO₃) is improved, preferably, the amount of ketone type organic solvent is reduced, which is used at the extraction of ^(99m)Tc, more preferably, the acid alumina obtained by processing the alumina with uniform particle diameter in 0.1M-HNO₃ for 24 hours or more is used, and more preferably, the diameter of a column in which the acid alumina is filled is set to Φ10-14 mm. Actually, the production method to obtain a large amount of high concentrated ^(99m)Tc solution was established by using rhenium (Re) of a homologous element of ^(99m)Tc, to which chemical property is similar. As a result, it came to be able to produce high-radioactivity ^(99m)Tc with 2.5 TBq (69 Ci) to 36 TBq (966 Ci).

Specifically, a method of producing high concentrated ^(99m)Tc solution according to one aspect of the present invention comprises the steps of:

dissolving ⁹⁹MoO₃ pellet with alkali solution;

extracting ^(99m)Tc from the solution with ketone type organic solvent;

separating an ketone type organic phase containing ^(99m)Tc and an aqueous phase;

adsorbing and concentrating the separated ketone type organic phase containing ^(99m)Tc after removing impurities through two kinds of alumina columns connected continuously (a basic alumina column for impurity removal and an acidic alumina column for adsorption and concentration); and

eluting ^(99m)Tc from the acidic alumina column to which ^(99m)Tc is adsorbed by physiological saline,

wherein said alkali solution is 6M-NaOH solution or 6M-KOH solution, and whereby the production efficiency is assumed to become maximum while keeping the quality of ^(99m)Tc solution the highest.

In the above-mentioned production method, it is desirable to use acid alumina prepared by processing alumina with uniform particle diameter in 0.1M-HNO₃ for 24 hours or more as alumina used for the acidic alumina column.

In the above-mentioned production method, it is desirable to set a diameter of the acidic alumina column which adsorbs ^(99m)Tc to the range of Φ10-14 mm.

According to a method of the present invention, an amount of the liquid used for dissolution of ⁹⁹MoO₃ pellet can be suppressed to the minimum amount and the efficiency of production be improved by using 6M-NaOH solution or 6M-KOH solution as alkali solution by which ⁹⁹MoO₃ pellet is dissolved.

In addition, high concentrated ^(99m)Tc with 2.5 TBq (69 Ci)-36 TBq (966 Ci), which is greatly different from the conventional unit of GBq is obtained in large quantities and in a short time. That is, it is possible to obtain ^(99m)Tc solution of the radioactive concentration equal to ^(99m)Tc solution obtained from ⁹⁹Mo produced by an (n,f) method.

BRIEF DESCRIPTION OF SEVERAL DRAWINGS

FIG. 1 shows a schematic view of ⁹⁹Mo/^(99m)Tc extraction-separation and concentration system.

FIG. 2 shows an elution curve of Re with an alumina column.

FIG. 3 shows the relationship between^(99m)Tc radioactivity estimated and recovery yield.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention separates and concentrates ^(99m)Tc at high efficiency while maintaining the high quality by using a ^(99m)Tc production unit in which a conventional method of extracting and separating ^(99m)Tc directly from the solution obtained by dissolving ⁹⁹MoO₃ pellets to MEK, and a conventional method of purifying and concentrating ^(99m)Tc with an alumina column are combined, and by optimizing the components and the quantities of various liquids used in the production process of ^(99m)Tc.

The design of each system was carried out to put this unit into practical use. The embodiments of this invention will be explained hereinafter. Here, NaOH was used as alkali solution for dissolving ⁹⁹MoO₃ pellet, and methyl ethyl ketone (MEK) was used as solution for extracting ^(99m)Tc from the dissolved solution. However, it is possible to use KOH which has a similar function instead of NaOH, and use other ketone type organic solvents such as acetones instead of MEK as explained in the above-mentioned patent literature 1.

Embodiment

FIG. 1 shows a schematic view of ⁹⁹Mo/^(99m)Tc extraction separation and concentration system according to the present invention. This system comprises mainly ⁹⁹MoO₃ pellet dissolving tank 10, ^(99m)Tc extraction tank 20, ^(99m)Tc separation tank 30, column 40 for impurity removal, and column 50 for ^(99m)Tc concentration. In addition, Each of the tanks and columns has a washing line, etc. to remove impurities which become the obstructions of the antibody labeling of ^(99m)Tc pharmaceutical products.

In ⁹⁹MoO₃ pellet dissolving tank 10 comprised of an Erlenmeyer flask, stirrer, etc. ⁹⁹MoO₃ pellet to which the neutrons are irradiated is dissolved in the alkali solution with stirrer. Moreover, in ^(99m)Tc extraction tank 20, ^(99m)Tc is extracted directly from ⁹⁹Mo solution to MEK using an agitator at high efficiency. Next, the obtained MEK phase containing ^(99m)Tc is moved to ^(99m)Tc separation tank 30 comprised of a separatory funnel, etc. and is separated into an MEK phase containing ^(99m)Tc and an aqueous phase of alkali solution to collect only MEK phase containing ^(99m)Tc. In column 40 for impurity removal in which the basic alumina is filled, impurities such as ⁹⁹Mo contained in MEK containing ^(99m)Tc are removed. In column 50 for ^(99m)Tc concentration in which acid alumina is filled, ^(99m)Tc is made to be adsorbed from the MEK phase containing ^(99m)Tc , and then the ^(99m)Tc is eluted by using a small amount of physiological saline and concentrated.

Here, acid alumina in which alumina with uniform particle diameter had processed in 0.1M-HNO3 for 24 hours or more was used as the above-mentioned acid alumina in the following tests. The diameter of column 50 for ^(99m)Tc concentration in which such acid alumina is filled is desirable within the range of Φ10-14 mm to improve the adsorption efficiency of ^(99m)Tc and elute ^(99m)Tc efficiently by using a small amount of physiological saline.

1) MoO₃ Dissolution Test by NaOH

The MoO₃ dissolution test to determine the solubility condition of the MoO₃ pellet to which the neutron was irradiated by NaOH solution was carried out in ⁹⁹MoO₃ pellet dissolving tank 10. First of all, while changing sequentially the concentration of NaOH, the NaOH was mixed with MEK, and stirred for 5 minutes. The concentration of NaOH was determined to 6M in light of the interface state etc. of the aqueous phase and the MEK phase. Though it is desirable that the concentration of this alkali solution is in a higher value such as 7M and 8M to decrease the entire volume and miniaturize the system, It has been understood from the experiment result that 6M is the best because the precipitation is caused after the dissolution when the concentration of the alkali solution exceeds 6M.

Next, MoO₃ was dissolved while changing sequentially the liquid volume of 6M-NaOH to determine an amount of 6M-NaOH necessary to dissolve MoO₃. As a result, the ratio of 100 ml to 50 g of MoO₃ was suitable.

2) Solvent Extraction Test by MEK

The solvent extraction to determine ^(99m)Tc extraction condition by MEK from the dissolved solution was tested in ^(99m)Tc extraction tank 20. The alkali solution and MEK were mixed and stirred for 5 minutes. Here, the liquid volume of MEK was changed sequentially. The aqueous phase and the MEK were separated and collected, and their capacities were measured. As a result, it was confirmed to be able to collect 90% or more of the MEK phase to 6M-NaOH 300 ml at MEK 60 ml. That is, it was possible to separate ^(99m)Tc into MEK phase efficiently and concentrate it when the ratio of MEK to 6M-NaOH solution is 5 to 1. The amount of MEK which is necessary can be decreased like this by the optimization of the concentration of NaOH.

3) Rhenium (Re) Elution Test from Alumina Column

The elution test was carried out by using Re which is a homologous element of ^(99m)Tc. Here, Re corresponding to 2.5 TBq (69 Ci)-36 TBq (966 Ci) of radioactivity of ^(99m)Tc was used. 30 ml of MEK was mixed with the solution in which Re is dissolved to 150 ml of 6M-NaOH, and the solvent was extracted. The MEK containing Re was passed through a basic alumina column and then through an acidic alumina column, to which Alumina is filled respectively by 5 g. Physiological saline was supplied at a flow rate of about 1 ml/min to the acidic alumina column which Re is adsorbed.

The Re elution curve is shown in FIG. 2 and the relationship between ^(99m)Tc radioactivity estimated and recovery yield is shown in FIG. 3. The result of FIG. 2 is obtained as follows. The alkali solution containing Re which corresponds to 2.5 TBq-36 TBq of radioactivity of ^(99m)Tc was extracted by MEK solution respectively for 5 minutes, and after leaving it at rest for 30 minutes, the MEK phase was purified by the basic alumina and Re was made to be adsorbed by the acid alumina. Re adsorbed to the acid alumina is eluted by using physiological saline. In the process, 2 ml or 3 ml of the physiological saline are supplied to the acid alumina, and an amount of Re in the liquid collected is measured by ICP-AES. FIG. 3 shows the result of carrying out the collection work up to total 30 ml. The Re elution rate designated in the ordinate is the ratio (%) of an amount of Re eluted to an amount of Re added in the beginning. Moreover, the graph of FIG. 3 showing the relationship between the ^(99m)Tc radioactivity estimated and the recovery yield illustrates how much recovery yield is obtained for each amount of Re which corresponds to 2.5 TBq-36 TBq of radioactivity of ^(99m)Tc.

Based on the elution curve, 3 ml of Initial effluent were thrown away and 12 ml in total from 4 ml to 15 ml of the effluent was recovered. As a result, it was able to be confirmed that Re can be collected in the recovery yield of 80% or more, and ^(99m)Tc solution is obtain, in which the concentration of ^(99m)Tc, that is, Re corrected, is ten times or more, compared with the original ⁹⁹Mo solution. In other words, it became possible to recover 2.5 TBq (69 Ci)-50 TBq (966 Ci) of radioactivity of ^(99m)Tc by 80% or more.

The evaporation operation of MEK for extracting ^(99m)Tc has required a long time in the prior art. In addition, products might color slightly due to the mixing of the aqueous phase with the MEK phase when the MEK phase and the aqueous phase is separated and recovered. Therefore, to avoid these problems, the coloring phenomenon of the product was prevented by purifying and concentrating MEK containing ^(99m)Tc with the alumina column in the present invention. There is a feature that this method can be handily processed in a short time.

Moreover, though a similar technique to the present invention cannot obtain more than about 18.5 GBq (500 mCi) so far, it was proven that the present invention can be applied to produce a ^(99m)Tc product with a large amount of radioactivity from 2.5 TBq (69 Ci) to 36 TBq (966 Ci) by clarifying the adsorption and the elution performance using Re of a homologous element of ^(99m)Tc and the same chemical property as ^(99m)Tc. 

1. A method of producing high concentrated ^(99m)Tc solution comprises the steps of: dissolving ⁹⁹MoO₃ pellet with alkali solution; extracting ^(99m)Tc from the dissolved solution with ketone type organic solvent; separating an ketone type organic phase containing ^(99m)Tc and an aqueous phase; adsorbing and concentrating the separated ketone type organic phase containing ^(99m)Tc after removing impurities, through a basic alumina column for impurity removal and an acidic alumina column for adsorption and concentration connected continuously; and eluting ^(99m)Tc from the acidic alumina column to which ^(99m)Tc is adsorbed by physiological saline, wherein said alkali solution is 6M-NaOH solution or 6M-KOH solution,
 2. The method according to claim 1, wherein an acid alumina prepared by processing alumina with uniform particle diameter in 0.1M-HNO₃ for 24 hours or more is used as alumina used for said acidic alumina column.
 3. The method according to claim 1, wherein a diameter of said acidic alumina column which adsorbs ^(99m)Tc is set to the range of Φ10-14 mm.
 4. The method according to claim 1, wherein said ketone type organic solvent is methyl ethyl ketone solution.
 5. The method according to claim 4, wherein a diameter of said acidic alumina column which adsorbs ^(99m)Tc is set to the range of Φ10-14 mm. 